If you haven’t done so already, read my blog post on understanding lab reference ranges - it puts the remainder of these posts into context.

In primary care, patients often request a variety of tests. It’s our responsibility to exercise due diligence and clinical judgment to assess the necessity of each diagnostic test. There’s no such thing as a benign test; incidental findings can lead us down the rabbit hole!

Thyroid function tests are commonly ordered in primary care for a variety of reasons. Let’s dive into the utility of serum TSH, free T4, and more.

Case: a 30-year-old woman presents with fatigue, low mood, and poor concentration. She asks for thyroid function tests, including free thyroid hormones and antibodies, after reading about their relevance for autoimmune thyroid disease. Notably, her sister has hypothyroidism. The patient is not pregnant and does not plan to conceive. She has regular menstrual cycles and does not take any medications.

While the differential diagnosis for fatigue and low mood is extensive, ordering a thyroid-stimulating hormone (TSH) test is reasonable to rule out hypothyroidism as part of her evaluation.

Pathophysiology Recap: Thyroid Review

The hypothalamus secretes thyrotropin releasing hormone. This stimulates the anterior pituitary gland to secrete thyroid stimulating hormone. This in turn stimulates the thyroid gland to secrete free T4 and free T3 for circulation in the body (1). Thyroid hormone affects the heart, central nervous system, autonomic nervous system, bone, gastrointestinal system and regulates metabolism (1).

When do we order TSH?

Based on clinical suspicion, we order TSH to assess for hypothyroidism or hyperthyroidism. In this case, we want to rule out hypothyroidism as a contributing factor to the patient’s fatigue and low mood.

Hypothyroidism

Common signs and symptoms: bradycardia, cold intolerance, constipation, fatigue, and weight gain (1).

Primary hypothyroidism: underactive thyroid gland secondary to Hashimotos thyroiditis (most common), iatrogenic (e.g. drug-induced), congenital, and decreased dietary iodine (2). The 2 major culprits for drug induced hypothyroidism are amiodarone and lithium. Patients taking these medications should have routine TSH monitoring (2).

Lab test interpretation: high TSH and low Free T4.

Secondary or tertiary hypothyroidism: problem with the pituitary or hypothalamus.

Lab interpretation: low TSH AND low Free T4.

Pearl # 1: Order TSH as a stand alone test when you have clinical suspicion for hypothyroidism or hyperthyroidism.

Lab References Range for Hypothyroidism

There is ongoing debate regarding the appropriate upper limit of normal for TSH levels; most laboratories set a cutoff between 4.5 and 5 mU/L. Additionally, TSH distribution varies with age, as older individuals may have higher TSH levels without exhibiting clinical disease (3).

Controversy also surrounds the management of patients with serum TSH values between 5 and 10 mU/L and normal free T4 levels, a condition known as subclinical hypothyroidism. Current evidence suggests that treatment does not significantly impact mortality, cardiovascular disease, weight, fatigue, cognitive function, or quality of life (3). Typically, no treatment is recommended for TSH levels between 4.5 and 10 mU/L with normal free T4. However, if TSH exceeds 10 mU/L with normal T4, it is advisable to recheck levels in 6 to 8 weeks. If TSH remains above 10, treatment should be considered if the patient is symptomatic (3).

• If the TSH is >10, this is generally indicative of hypothyroidism requiring treatment (2).

• If the TSH is 4-10, this is generally indicative of subclinical hypothyroidism (2).

Pregnancy Considerations: Subclinical Hypothyroidism and Hypothyroidism

Recent evidence from large, high-quality randomized controlled trials consistently demonstrates that levothyroxine treatment for pregnant women with subclinical hypothyroidism offers no benefit to either the mother or the child (4). As a result, universal screening for hypothyroidism during pregnancy is not necessary. However, treating overt hypothyroidism in pregnancy is crucial, as poorly controlled hypothyroidism has been linked to various complications, including miscarriage, preterm labor, gestational hypertension and diabetes, preeclampsia, fetal cognitive impairment, lower IQ scores, stillbirth, and low birth weight (2).

Reference Ranges in Pregnancy for Hypothyroidism

Women with established hypothyroidism have different TSH targets throughout pregnancy, and require frequent monitoring and adjustments as necessary for the following TSH targets (5).

• First trimester: 0.1-2.5

• Second trimester: 0.2-3.0

• Third trimester: 0.3-3.0

Monitoring during pregnancy: Monitor TSH and free T4 at minimum every 4 weeks during the first half of pregnancy and at least once between 26-32 weeks (2).

Hyperthyroidism

Common signs and symptoms: weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness (1).

Causes: increased thyroid gland function secondary to Grave’s Disease, solitary toxic nodules or toxic multinodular goiter, or thyroiditis (2).

Reference ranges for Hyperthyroidism

• If the TSH is <0.3, this is indicative of subclinical hyperthyroidism (2)

• If the TSH is <0.1, this is indicative of hyperthyroidism (2)

Pearl # 2: patients taking more than 10mg of biotin should hold the supplement for 2 days prior to assessing TSH, as it can interfere with the lab results (3). Biotin can result in falsely low levels of TSH and falsely high levels of Free T4 and Free T3.

When do we Order Free T4 and Free T3?

Back to the case: you order serum TSH and the result is 15.

• If TSH is normal: no further testing should be performed (3).

• If TSH is high: Free T4 can be added to determine the degreeof hypothyroidism. Free T3 is not helpful for the diagnosis of hypothyroidism (2,3).

• If TSH is low: free T4 and Τ3 are ordered to determine the degree of hyperthyroidism or to assess for secondary or tertiary hypothyroidism (2,3).

Pearl # 3: Free T3 is not helpful for diagnosing hypothyroidism.

Two exceptions to these recommendations:

1. Measure TSH and free Т4 initially if pituitary or hypothalamic disease is suspected which can lead to impaired or absent TSH release (e.g., a young woman with amenorrhea and fatigue) (3).

2. Measure free Т4 if the patient has symptoms of hyper- or hypothyroidism despite a normal TSH result (3).

Reference range for total T4: it vary among laboratories; a typical reference range for total T4 is 4.6 to 11.2 mcg/dL (60 to 145 nmol/L) (3). Other reference ranges have been reported as 9-19 pmol/L (2).

Reference range for total T3:  it is even more variable among laboratories than that for total Τ4. A typical range is approximately 75 to 195 ng/dL (1.1 to 3 nmol/L) (3). Other references ranges report a normal range of 2.6-5.7pmol/L (2).

Back to the case: You order Free T4 and the result is 5. You diagnose her with hypothyroidism likely secondary to Hashimoto’s thyroiditis and discuss treatment with levothyroxine.

Tips for Monitoring Response to Treatment of Hypothyroidism

• Re-evaluate TSH and free T4 every 4-8 weeks until stable (2).

• TSH can be unreliable for months, Free T4 is a more reliable indicator of treatment response initially (2).

• Clinical improvement should occur in 2 weeks (2).

• Once euthyroid, monitor TSH every 6-12 months (2).

• Re-evaluate TSH every 4-8 weeks after any change in levothyroxine brand/dose or any change in weight of >20lb (3).

When Should we Order Thyroid Antibodies?

The short answer: never or rarely. Routine measurement of thyroid antibodies does not help assess thyroid function, nor does it inform treatment in the primary care setting. Several antibodies against thyroid antigens have been described in chronic autoimmune thyroiditis and Graves' disease (3).

Thyroglobulin (Tg, formerly known as the colloid antigen): Patients with Hashimoto's thyroiditis or Graves' disease may have thyroglobulin antibodies, but thyroglobulin antibodies do not need to be measured to diagnose autoimmune thyroid disease (3).

Thyroid peroxidase (TPO): Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies. Do not measure serum anti-TPO antibodies in patients with overt primary hурοthyrоiԁism, because almost all have chronic autoimmune thyroiditis. Anti-TPO antibodies may be useful to predict the likelihood of progression to permanent overt hурοthуrоidism in patients with subclinical hурοthуroidism (3). Instead of ordering antibodies, you can periodically re-check serum TSH and clinical symptoms.

Thyrotropin receptor antibodies (TRAbs): are classified as stimulating, blocking, or neutral. Thyroid-stimulating immunoglobulins cause Graves' disease. Thyroid receptor-blocking antibodies can cause hурοthyrоiԁism (3). It is not necessary to diagnose hypo or hyper-thyroidism.

Pearl # 4: Thyroid antibodies do not help diagnose hypothyroidism or hyperthyroidism. Think twice before ordering these tests.

Back to the case: you explain no further lab testing is required, as it will not alter the diagnosis or change treatment.

Key Take Home Points:

• TSH is used to assess for hypothyroidism or hyperthyroidism.

• If you are clinically suspicious of these diagnoses, order TSH as a stand alone test first. Avoid reflex testing of free T4 and free T3.

• If TSH is normal, only order free Т4 if the patient has overt symptoms of hyper- or hурοthуroidiѕm and your clinical suspicion is high. Ensure the patient is not taking biotin.

• If TSH is >10, order free T4 to assess the degree of hypothyroidism.

• If TSH is <0.1, order free T4 and free T3 to assess for hyperthyroidism or to assess for secondary or tertiary hypothyroidism.

References

Shahid MA, Ashraf MA, Sharma S. Physiology, Thyroid Hormone. [Updated 2023 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK500006/

University of Saskatchewan, College of Pharmacy and Nutrition. (2021). RxFiles Drug Comparison Charts: Thyroid Disorders Overview. 13th Ed.

Ross, D. S. Laboratory assessment of thyroid function. In: UpToDate, Eidt Cooper, DS, Mulder JE (Ed). Wolters Kluwer. Accessed October 10, 2024.

Yamamoto JM, Metcalfe A, Nerenberg KA, Khurana R, Chin A, Donovan LE. Thyroid function testing and management during and after pregnancy among women without thyroid disease before pregnancy. CMAJ. 2020 Jun 1;192(22):E596-E602. doi: 10.1503/cmaj.191664. PMID: 32575048; PMCID: PMC7272194.

Carney LA, Quinlan JD, West JM. Thyroid disease in pregnancy. Am Fam Physician. 2014 Feb 15;89(4):273-8. Erratum in: Am Fam Physician. 2014 Jul 1;90(1):8. Dosage error in article text. PMID: 24695447.